Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues

Abstract

The present invention provides novel diphenyl ethene compounds and pharmaceutically-acceptable salts thereof. Also provided are methods for making the compounds of the invention as well as methods for the use thereof in the treatment of immune, inflammatory, and auto-immune diseases.

1. A compound of the following formula, or a salt thereof 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of unsubstituted or substituted alkyl with carbon between 1 and 18; alkenyl with carbon between 2 and 18; alkynyl with carbon between 2 and 18; halo, and COR 9 ; 
 R 2  and R 3  are independently selected from the group consisting of H, unsubstituted or substituted alkyl with carbon between 1 and 18, and acyl with carbon between 1 and 18; 
 R 4 , R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of H, unsubstituted or substituted alkyl with carbon between 1 and 18, alkenyl with carbon between 2 and 18, alkynyl with carbon between 2 and 18, aryl or aralkyl group, chloro, bromo, iodo, fluoro, nitro, CN, COR 9 , NR 10 R 11 , S(O) 2 NR 10 R 11 , SR 10 , SOR 10 , SO 2 R 10 , and OR 12 ; with the proviso that at least one of R 4 , R 5 , R 6 , R 7 , and R 8  is fluoro; 
 R 9  is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl, or NR 10 R 11 , or OR 10 ; 
 R 10  and R 11  are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl and aralkyl; 
 R 12  is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl and acyl; and 
 wherein the configuration of the double bond of the compound of Formula I is E or Z. 
 
     
     
       2. The compound of  claim 1 , wherein R 1  is isopropyl. 
     
     
       3. The compound of  claim 2 , wherein R 4 , R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of F, H, COOR 10 , and OR 12 , provided that one or more than one of R 3 , R 4 , R 5 , R 6 , R 7  and R 8  is COOR 10  or OR 12  and at least one of R 4 , R 5 , R 6 , R 7  and R 8  is fluoro. 
     
     
       4. The compound of  claim 2 , wherein R 2  and R 3  are independently selected from the group consisting of H, methyl and acetate. 
     
     
       5. A compound selected from the group consisting of:
 2-(3,5-dimethoxy-4-i-propylphenyl)-1-(2-fluorophenyl)ethene; 
 1-(3,5-dimethoxy-4-i-propylphenyl)-2-(3-fluorophenyl)ethene; 
 1-(3,5-dimethoxy-4-i-propylphenyl)-2-(4-fluorophenyl)ethene; 
 2-(3,5-difluorophenyl)-1-(3,5-dimethoxy-4-i-propylphenyl)ethene; 
 1-(2,4-difluorophenyl)-2-(3,5-dimethoxy-4-i-propylphenyl)ethene; 
 1-(2,6-difluorophenyl)-2-(3,5-dimethoxy-4-i-propylphenyl)ethene; 
 1-(3,5-dimethoxy-4-i-propylphenyl)-2-(2,4,6-trifluorophenyl)ethene; 
 1-(3,5-dimethoxy-4-i-propylphenyl)-2-(2,3,4,5,6-pentafluorophenyl)ethene; 
 5-[2-(2-fluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol; 
 5-[2-(3-fluorophenyl)ethenyl]-2-i-propylphenyl-1,3-diol; 
 5-[2-(4-fluorophenyl)ethenyl]-2-i-propylphenyl-1,3-diol; 
 5-[2-(3,5-difluorophenyl)ethenyl]-2-i-propylphenyl-1,3-diol; 
 5-[2-(2,4-difluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol; 
 5-[2-(2,6-difluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol; 
 2-i-propyl-5-[2-(2,4,6-trifluorophenyl)ethenyl]-1,3-benzenediol, and 5-[2-(2,3,4,5,6-pentafluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol. 
 
     
     
       6. The compound of  claim 1 , wherein the configuration of the double bond of the compound of Formula I is E. 
     
     
       7. The compound of  claim 1 , wherein the configuration of the double bond of the compound of Formula I is Z. 
     
     
       8. A pharmaceutical composition comprising: a compound of the following formula or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of unsubstituted or substituted alkyl with carbon between 1 and 18; unsubstituted or substituted cyclic alkyl with carbon between 3 and 18; alkenyl with carbon between 2 and 18; alkynyl with carbon between 2 and 18; halo, and COR 9 ; 
         R 2  and R 3  are independently selected from the group consisting of H, unsubstituted or substituted alkyl with carbon between 1 and 18, and acyl with carbon between 1 and 18; 
         R 4 , R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of H, unsubstituted or substituted alkyl with carbon between 1 and 18, alkenyl with carbon between 2 and 18, alkynyl with carbon between 2 and 18, aryl or aralkyl group, chloro, bromo, iodo, fluoro, nitro, CN, COR 9 , NR 10 R 11 , S(O) 2 N NR 10 R 11 , SR 10 , SOR 10 , SO 2 R 10 , and OR 12 , with the proviso that at least one of R 4 , R 5 , R 6 , R 7  and R 8  is fluoro; 
         R 9  is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl, NR 10 R 11 , and OR 10 ; 
         R 10  and R 11  are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl and aralkyl; 
         R 12  is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl and acyl; wherein the configuration of the double bond of the compound of Formula I is E or Z; and 
         a pharmaceutically acceptable diluent or carrier. 
       
     
     
       9. The pharmaceutical composition of  claim 8 , wherein R 1  is unsubstituted or substituted alkyl with carbon between 1 and 18. 
     
     
       10. The pharmaceutical composition of  claim 8 , wherein R 1  is halo group. 
     
     
       11. The pharmaceutical composition of  claim 9  or  claim 10 , wherein R 4 , R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of F, H, COOR 10 , and OR 12 , with the proviso that at least one of R 4 , R 5 , R 6 , R 7  and R 8  is fluoro. 
     
     
       12. The pharmaceutical composition of  claim 9  or  claim 10 , wherein R 2  and R 3  are independently selected from the group consisting of H, methyl and acetate. 
     
     
       13. The pharmaceutical composition of  claim 8 , wherein R 1  is isopropyl. 
     
     
       14. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
 2-(3,5-dimethoxy-4-i-propylphenyl)-1-(2-fluorophenyl)ethene; 
 1-(3,5-dimethoxy-4-i-propylphenyl)-2-(3-fluorophenyl)ethene; 
 1-(3,5-dimethoxy-4-i-propylphenyl)-2-(4-fluorophenyl)ethene; 
 2-(3,5-difluorophenyl)-1-(3,5-dimethoxy-4-i-propylphenyl)ethene; 
 1-(2,4-difluorophenyl)-2-(3,5-dimethoxy-4-i-propylphenyl)ethene; 
 1-(2,6-difluorophenyl)-2-(3,5-dimethoxy-4-i-propylphenyl)ethene; 
 1-(3,5-dimethoxy-4-i-propylphenyl)-2-(2,4,6-trifluorophenyl)ethene; 
 1-(3,5-dimethoxy-4-i-propylphenyl)-2-(2,3,4,5,6-pentafluorophenyl)ethene; 
 5-[2-(2-fluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol; 
 5-[2-(3-fluorophenyl)ethenyl]-2-i-propylphenyl-1,3-diol; 
 5-[2-(4-dluorophenyl)ethenyl]-2-i-propylphenyl-1,3-diol; 
 5-[2-(3,5-difluorophenyl)ethenyl]-2-i-propylphenyl-1,3-diol; 
 5-[2-(2,4-difluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol; 
 5-[2-(2,6-difluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol; 
 2-i-Propyl-5-[2-(2,4,6-trifluorophenyl)ethenyl]-1,3-benzenediol, and 
 5-[2-(2,3,4,5,6-pentafluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol. 
 
     
     
       15. The pharmaceutical composition of  claim 8 , wherein the configuration of the double bond of the compound of Formula I is E. 
     
     
       16. The pharmaceutical composition of  claim 8 , wherein the configuration of the double bond of the compound of Formula I is Z. 
     
     
       17. The composition of  claim 8 , wherein R 4 , R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of H and F, with the proviso that at least one of R 4 , R 5 , R 6 , R 7  and R 8  is F. 
     
     
       18. The composition of  claim 8 , wherein R 4 , R 5 , R 6 , R 7  and R 8  are H.